Different doses of BI 1467335 compared to placebo in patients with clinical evidence of NASH

Phase 1

• Conditions: on-alcoholic steatohepatitis; MedDRA version: 20.0 Level: PT Classification code 10076331 Term: Steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders; Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

• Registration Number: EUCTR2016-000499-83-IE
• Lead Sponsor: Boehringer Ingelheim Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-05-05
• Last Update Posted: 25 November 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 108

Inclusion Criteria

1. Clinical evidence of NASH defined as a. histological evidence of NASH (no more than 3 years prior to screening) OR b. clinical imaging results suggestive of NASH (no more than 3 years prior to screening OR within the screening phase, imaging procedures performed as per local standard)
i. evidence of hepatic steatosis >5% measured by the MRI-PDFF or assessed as steatosis (raised echogenicity of the liver parenchyma) by ultrasound AND ii. evidence of liver fibrosis defined as mean stiffness > 3.64 kPa as measured by the MRE protocol or mean stiffness > 7.2 kPa as measured by ultrasound based transient elastography (Fibroscan®)
2. Increased ALT defined as
a. ALT >1.5 ULN at screening and ALT >1.25 ULN in a local lab within 1 week to 3 months prior screening OR
b. Historic ALT > 1.25 ULN more than 3 months prior to screening and two consecutive ALT > 1.5xULN must be confirmed at least 1 week apart within the screening period
3. Age = 18 and =75 years at screening
4. BMI =25kg/m2 and <45kg/m2 at screening
5. Stable body weight defined as less than 5% change in body weight in the 3 months prior to screening while being treated with the standard of care and not treated with anti-obesity medication at screening.
6. Treatment with Antidiabetic concomitant medication including any insulin regimen needs to be stable for 3 months, and treatment with vitamin E needs to be stable for 6 months prior to informed consent and expected to be stable throughout the trial. All other concomitant medication has to be stable for at least 4 weeks prior screening. Concomitant medications taken to treat acute conditions (e.g. headache, sinusitis) for a short period (< 7 days) are permissible, if not otherwise prohibited.
For restricted medications please refer to section 4.2.2.1.
7. For female patients: Women of childbearing potential* must be willing and able to use two methods of contraception, at least one of which must be a highly effective method of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly .
Highly effective methods of birth control per ICH M3(R2) are:
• Combined (oestrogen and progestogen containing) hormonal birth control associated
with inhibition of ovulation. This may be oral, intravaginal or transdermal.
• Progestogen-only hormonal birth control associated with inhibition of ovulation. This
may be oral, injectable or implantable.
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS).
• Vasectomized sexual partner – provided that the partner is the sole partner of the
WOCBP and the vasectomised partner has received medical assessment of the surgical
success.
• True abstinence from male-female sex. This is defined as being in line with the preferred
and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the duration of
exposure to IMP; and withdrawal are not acceptable.
* A woman is considered of childbearing potential (WOCBP), i.e. fer

Exclusion Criteria

1. Current or history of significant alcohol consumption (defined as intake of >210g/week in males and >140g/week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on investigator judgement.
2. Prior participation in an interventional NASH trial 6 months before baseline or 5 times halflife of the investigational drug, whichever is longer.
3. Prior or planned bariatric surgery during study conduct, except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body weight within the last 12 months.
4. Use of drugs historically associated with liver injury, hepatic steatosis or steatohepatitis in the 4 weeks prior to screening; please refer to section 4.2.2.
5. History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (e.g. ascites, hepatic encephalopathy, variceal bleeding, etc.) or history of other forms of chronic liver disease (for example Hepatitis B, Hepatitis C, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, A1At deficiency, history of liver transplantation).
6. Active known chronic or relevant acute infections, such as HIV (Human Immunodeficiency Virus), \viral hepatitis, or tuberculosis. QuantiFERON® TB test and HBs Ag test will be performed during screening. Patients with a positive test result may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active infection.
7. Solid liver lesions other than haemangiomas. a. Suspicion or diagnosis or history of hepatocellular carcinoma (HCC)
8. eGFR <60ml/min/1.73m2 at screening (CKD-EPI formula).
9. ALT >5.0 ULN at screening.
10. Platelet count < 150.000/µL
11. Bilirubin level > ULN (except for known Gilbert´s disease with a conjugated bilirubin of < 0.3 mg/dL))
12. Uncontrolled diabetes defined as an HbA1c =9.5% in the 3 months prior to or at screening.
13. Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic , psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the investigator, are likely to interfere with the analyses of safety and efficacy in this study. Patients with an expected life expectancy of less than 2 years are also excluded.
14. Major surgery (major according to the investigator’s assessment) performed within 12 weeks prior to randomisation or planned during study conduct, e.g. hip replacement.
15. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
16. Patients who must or wish to continue the intake of restricted medications (see section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
17. Previous randomisation in this trial.
18. Currently enrolled in another investigational device or dr

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is the proof of mechanism and support of dose finding, together with the safety evaluation in patients with clinical evidence of NASH. ;Secondary Objective: Effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, AP, Gamma-GT and CK18 fragments). Safety will be assessed throughout the study to provide key information regarding the use of BI 1467335 in patients with NASH.;Primary end point(s): 1) Plasma amine oxidase copper-containing 3 (AOC3) activity relative to baseline in %, 24 h post dose, after 12 weeks of treatment.;<br> Timepoint(s) of evaluation of this end point: 1) 24 hours <br>

Secondary Outcome Measures

Name	Time	Method
<br> Secondary end point(s): 1) Percentage of subjects with adverse reactions. <br> 2) relative ALT change from baseline <br> 3) relative AST change from baseline <br> 4) relative AP change from baseline <br> 5) relative Gamma-GT change from baseline <br> 6) relative caspase cleaved cytokeratin 18 (M30) change from baseline <br> 7) relative total cytokeratin 18 (M65) change from baseline<br> ;<br> Timepoint(s) of evaluation of this end point: 1) 16 weeks <br> 2) 12 weeks <br> 3) 12 weeks <br> 4) 12 weeks<br> 5) 12 weeks <br> 6) 12 weeks <br> 7) 12 weeks<br>